Development of Hsp90 Isoform- Selective Inhibitors as a Novel Opioid Dose-Reduction Therapy

开发 Hsp90 异构体选择性抑制剂作为新型阿片类药物剂量减少疗法

基本信息

批准号：
10294366
负责人：
John Michael Streicher
金额：
$ 65.79万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10294366
关键词：
ABCB1 gene Absence of pain sensation Acute Pain Affect Affinity Analgesics Binding Proteins Bioavailable Biological Availability Brain Chronic Clinical Constipation Crystallization Cytochrome P450 Data Dependence Development Dose Drug Kinetics Drug usage Fluorescence Polarization Generations Goals HIV HSP 90 inhibition Health Heat-Shock Proteins 90 Human In Vitro Individual Investigation Lead Liver Microsomes MDCK cell Medical Methods Modernization Morphine Mus Neuropathy Nociception Opioid Opioid Analgesics Opioid Receptor Oral Oral Administration Overdose Oxycodone Pain Pain management Patients Performance Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Plasma Proteins Play Protein Isoforms Proteins Public Health Quality of life Receptor Signaling Regulation Rewards Role Signal Transduction Solubility Spinal Spinal Anesthesia Spinal Cord Structure Surgical incisions Tail Techniques Testing Therapeutic Toxic effect Toxicity Tests United States Ventilatory Depression Work addiction analog aqueous base chronic pain chronic pain management cost improved in vivo in vivo evaluation inhibitor/antagonist molecular modeling morphine tolerance mu opioid receptors novel novel drug class novel strategies novel therapeutics opiate tolerance opioid abuse opioid epidemic opioid therapy pain model patient population response scaffold side effect small molecule social

项目摘要

ABSTRACT The management of chronic pain is clinically challenging, and relies heavily on opioid drugs like morphine and oxycodone. However, opioids are plagued by numerous side effects that impact quality of life, like tolerance, constipation, and reward/addiction, contributing to an opioid abuse, addiction, and overdose crisis. These clinical and social challenges highlight the vast medical need for new approaches to pain management. To this end, we have pioneered an investigation into the role of Heat shock protein 90 (Hsp90) in regulating opioid signal transduction, anti-nociception, and side effects. We have found that Hsp90 regulates mu opioid receptor (MOR) signal transduction to different effect in brain vs. spinal cord. In brain, Hsp90 promotes MOR signaling and anti- nociception, so that Hsp90 inhibition in brain blocks opioid anti-nociception. In spinal cord, Hsp90 blocks MOR signaling and anti-nociception, so that Hsp90 inhibition in spinal cord enhances opioid anti-nociception. In further studies, we found that Hsp90 inhibition in spinal cord increases morphine anti-nociceptive potency 2-3 fold in acute and chronic pain, reduces tolerance and rescues established tolerance, all without altering the potency of constipation and reward. These results suggest that spinal Hsp90 inhibition could be used as an opioid dose-reduction strategy, to improve or maintain analgesic efficacy while reducing side effects. However, one challenge to this approach is our finding that non-selective Hsp90 inhibitors, when given systemically, gave results similar to the brain, blocking opioid anti-nociception. Seeking a way around this limitation, we found that Hsp90 isoforms differ between brain and spinal cord, with Hsp90α alone acting in brain while Hsp90α, Hsp90β, and Grp94 all act in spinal cord. Hypothesizing that an isoform-selective Hsp90 inhibitor could be used to target spinal cord-specific isoforms, we found that the Hsp90β-selective inhibitor KUNB106 enhanced morphine anti- nociception while rescuing established morphine tolerance when given systemically. These results strongly suggest that Hsp90β-selective inhibitors could be used as a novel, first-in-class opioid dose-reduction therapy. However, KUNB106 is a first generation compound, with poor solubility and pharmacokinetics (PK) and an uncertain therapeutic profile. In this proposal, we will thus optimize KUNB106 to create a new therapeutic to enhance opioid therapy and reduce opioid side effects like reward/addiction. In Aim 1 we will utilize cutting edge medicinal chemistry approaches using Hsp90 isoform co-crystallized structures to create optimized compounds based on the KUNB106 scaffold. In Aim 2, we will test these compounds for Hsp90 isoform selectivity, ADMET parameters, off-target interactions, and in vivo PK in mice, aiming to identify highly selective, soluble, and orally bioavailable compounds. In Aim 3, we will test the best of these compounds for their efficacy in enhancing opioid anti-nociception in acute and chronic pain models in mice, while reducing tolerance, constipation, reward, and respiratory depression. Top candidates will be tested for off-target side effects and toxicity. Through this project, we aim to create optimized candidates for further development as new therapeutics for patient pain management.

抽象的慢性疼痛的治疗在临床上具有挑战性，并严重依赖于吗啡等阿片类药物和羟考酮。但是，阿片类药物受到影响的众多副作用的困扰，这些副作用会影响生活质量，例如宽容，这些临床社会挑战强调了对疼痛管理新方法的广泛医疗需求。为此，我们是否率先研究了热激蛋白90（HSP90）在调节阿片类药物信号中的作用转导，抗伤害感受和副作用。我们发现HSP90调节阿片类药物受体（MOR）信号转导向大脑与脊髓的不同作用。在大脑中，HSP90促进了MOR信号传导和抗伤害感受，因此脑中的Hsp90抑制作用会阻断OOid抗伤害感受。在脊髓中，HSP90阻止MOR 信号传导和抗伤害感受，因此脊髓中的HSP90抑制会增强OOID抗伤害感受。进一步研究，我们发现脊髓中的HSP90抑制会增加吗啡抗伤害感受2-3倍在急性和慢性疼痛中，降低了耐受性和救援，建立了耐受性，而无需改变便秘和奖励的效力。这些结果表明脊柱HSP90抑制作用可以用作阿片类药物减少策略，以提高或维持镇痛效率，同时降低副作用。然而，这种方法的一个挑战是我们发现非选择性HSP90抑制剂在系统地给出时，给予结果与大脑相似，阻止了阿片类药物的抗伤害感受。寻求解决这一限制的方法，我们发现 HSP90在大脑和脊髓之间不同的同工型，HSP90α仅作用于大脑，而Hsp90α，Hsp90β， GRP94全部在脊髓中起作用。假设同工型选择性HSP90抑制剂可用于靶向脊髓特异性同工型，我们发现HSP90β选择性抑制剂KUNB106增强了吗啡抗在拯救系统时，伤害感受到了吗啡的耐受性。这些结果强烈表明HSP90β选择性抑制剂可以用作一种新型的一类阿片类药物剂量还原疗法。但是，Kunb106是第一代化合物，溶解度和药代动力学（PK）和一个不确定的治疗特征。在此建议中，我们将优化Kunb106，以创建一种新的疗法增强阿片类药物疗法并减少阿片类药物副作用，例如奖励/成瘾。在AIM 1中，我们将利用前沿使用HSP90同工型共结晶结构来创建优化化合物的药物化学方法基于Kunb106脚手架。在AIM 2中，我们将针对HSP90同工型选择性测试这些化合物，ADMET 小鼠中的参数，非目标相互作用以及体内PK，旨在识别高度选择性，可溶性和口服生物利用化合物。在AIM 3中，我们将测试这些化合物中最好的效率，以增强Ooid 小鼠的急性和慢性疼痛模型中的抗伤害感受，同时降低耐受性，便秘，奖励和呼吸抑郁。顶级候选人将接受脱靶副作用和毒性测试。通过这个项目，我们旨在创建优化的候选人，以作为患者疼痛管理的新疗法。